Substituted imidazopyridine and triazolopyridine compounds as negative allosteric modulators of mGluR5

A method for the treatment of a neurological and/or phychiatric disorder associated with glutamate dysfunction in a mammal wherein the disorder is selected from autism spectrum disorder, depression, stroke, head trauma, dementia, Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, idiopathic Parkinson's disease, drug induced Parkinson's disease, migraine, addictive behavior, withdrawal from addictive substances, anxiety, mood disorder, and tardive dyskinesia, the method comprising the step of administering to the mammal a therapeutically effective amount of a compound having a structure represented by a formula:

• wherein Q is selected from N and CR5;
• wherein R5, when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR30, —NR31aR31b, —SO2R32, and —(C═O)R33;
• wherein R30, when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl;
• wherein each of R31a and R31b), when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl;
• or wherein R31a and R31b, when present, are optionally covalently bonded and, together with the nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle;
• wherein R32, when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and —NR34aR34b;
• wherein each of R34a and R34b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl;
• or wherein R34a and R34b, when present, are optionally covalently bonded and, together with the nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle;
• wherein R33, when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and —NR35aR35b;
• wherein each of R35a and R35b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl;
• or wherein R35a and R35b, when present, are optionally covalently bonded and, together with the nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle;
• wherein each of Z1 and Z2 is independently selected from N and CR6, provided that Z1 and Z2 are not simultaneously N;
• wherein each of R6, when present, is independently selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR40, —NR41aR41b, —SO2R42, and —(C═O)R43;
• wherein R40, when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl;
• wherein each of R41a and R41b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl;
• or wherein R41a and R41b, when present, are optionally covalently bonded and, together with the nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle;
• wherein R42, when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and —NR44aR44b;
• wherein each of R44a and R44b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl;
• or wherein R44a and R44b, when present, are optionally covalently bonded and, together with the nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle;
• wherein R43, when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and —NR45aR45b;
• wherein each of R45a and R45b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl;
• or wherein R45a and R45b, when present, are optionally covalently bonded and, together with the nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle;
• wherein R1 is heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from deuterium, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR60, —NR61aR61b, —SO2R62, and —(C═O)R63;
• wherein each occurrence of R60, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl;
• wherein each occurrence of each of R61a and R61b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl;
• or wherein R61a and R61b, when present, are optionally covalently bonded and, together with the nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle;
• wherein each occurrence of R62, when present, is independently selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and —NR64aR64b;
• wherein each occurrence of each of R64a and R64b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl;
• or wherein R64a and R64b, when present, are optionally covalently bonded and, together with the nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle;
• wherein each occurrence of R63, when present, is independently from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and —NR65aR65b;
• wherein each occurrence of each of R65a and R65b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl;
• or wherein R65a and R65b, when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle;
• wherein R2 is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl;
• wherein each of R3a, R3b, R3c, and R3d, is independently selected from hydrogen and fluoro:
• or a pharmaceutically acceptable salt thereof.